Recent advances in our understanding of the replicative mechanism of HBV, and the development of potent nucleoside analogues as clinically effective inhibitors of the HIV reverse transcriptase or herpesvirus polymerases has opened a new era in the treatment of chronic HBV infection. There is now a logical basis for combination therapy, because of the clear need for prolonged treatment and the associated possibility that drug resistant strains will emerge with monotherapy, but the choice of agents to combine and the regimens in which they should be employed remain uncertain. We have performed a preliminary study to assess the safety and to obtain preliminary information on the efficacy of the combination of alpha interferon with famciclovir. In this study, we treated patients with chronic HBV infection who had failed previous interferon alfa therapy, with an overlapping regimen of interferon alfa and famciclovir therapy totaling 20 weeks. This study is now closed. We are in the final stages of planning a multicenter, double blind, placebo-controlled study comparing the combination of famciclovir with lamivudine with lamivudine alone. The objectives of this study are to determine the safety, tolerance, pharmacokinetics, and preliminary efficacy of combination therapy over 48 weeks in a total of 40 patients with chronic HBV infection. This study is being developed in collaboration with the NIAID Collaborative Antiviral Study Group.